CN102871977A - Ulipristal acetate dispersible tablet and preparation method thereof - Google Patents

Abstract

The invention relates to a ulipristal acetate preparation and a preparation method thereof, and particularly relates to a ulipristal acetate dispersible tablet with improved dissolution rate and a preparation method thereof. In order to solve the problem that the ulipristal acetate tablet in the prior art is low in dissolution rate and bioavailability and affects emergency contraception effects, the invention provides the ulipristal acetate dispersible tablet. The ulipristal acetate dispersible tablet is prepared from a premix compound of ulipristal acetate and a disintegrating agent and a excipient, wherein the content of ulipristal acetate is 1-30%(w/w) and accounts for 50-80% of the total weight of the premix compound, the particle sizes of 70-100% ulipristal acetate and the disintegrating agent are less than or equal to 75 micrometers. The ulipristal acetate dispersible tablet disclosed by the invention can take effect quickly in vivo, can realize more effective emergency contraception effect, and is wider in application range.

Description

Ulipristal acetate dispersible tablet and preparation method thereof

Technical field

The present invention relates to preparation of ulipristal acetate and preparation method thereof, be specifically related to ulipristal acetate dispersible tablet of dissolution raising and preparation method thereof.

Background technology

Ulipristal acetate (ulipristal acetate) has another name called: CDB-2914, chemistry 17 α by name-acetoxyl group-11 β-[4-(N, the N-dimethylamino)-phenyl]-19-norpregna-4,9-diene-3, the 20-diketone is a kind of steroidal gestation.Can be used for the emergency contraception of unprotect sexual intercourse in 120 hours or contraceptive failure, low dosage is taken for the routine contraception every day, also can be used for treating hysteromyoma.The product ella (30mg ulipristal acetate sheet) that has gone on the market at present is used for emergency contraception, and CN200980149309 discloses the ulipristal acetate sheet, ulipristal acetate process micronization processes.But because the water solublity of ulipristal acetate is poor, the ordinary tablet of making behind the micronization in vivo dissolution rate is still lower, and bioavailability is relatively low, affects the emergency contraception effect.

Emergency contraception is more early taken, more early onset, and contraceptive effect is better.Therefore in order to improve the emergency contraception effect of ulipristal acetate, need bioavailability to improve, onset effect faster dosage form occurs.

Dispersible tablet is a kind of novel quick-effective preparation, both can be directly oral, but also rapid dispersion is drunk after in water, with respect to conventional tablet and capsule have taking convenience, absorb fully rapidly, the special performance such as bioavailability is high and untoward reaction is little.

Medicine generally all will be through micronization processes when the preparation dispersible tablet, and size should be below 100 microns.Though drug micronization can reduce the granularity of powder, increase specific surface area, along with the increase of surface area, the surface free energy of particle also increases thereupon, the rear free energy that acquires a certain degree can lower automatically, and small-particle can reassemble again, has hindered on the contrary the stripping of medicine.The pharmaceutic adjuvants of the large usage quantities such as insoluble drug and filler that adopt are pre-mixed or jointly grind the appearance of avoiding this problem more in the prior art.

Summary of the invention

Low in order to solve in the prior art ulipristal acetate sheet dissolution and bioavailability, affect the problem of emergency contraception effect, the invention provides and a kind ofly can make in vivo rapidly onset of ulipristal acetate, emergency contraception is more effective, and the wider ulipristal acetate dispersible tablet of the scope of application.

The technical scheme that realizes the object of the invention is:

The ulipristal acetate dispersible tablet comprises:

The premix material of ulipristal acetate and disintegrating agent, ulipristal acetate content are 1-30% (w/w);

Filler: one or more in sucrose, dextrin, lactose, mannitol, sorbitol, microcrystalline Cellulose, starch, calcium sulfate, the calcium hydrogen phosphate, filler content are 10-90% (w/w);

Disintegrating agent: one or more in polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, microcrystalline Cellulose, starch and the derivant thereof;

Binding agent: one or both in polyvidone and aqueous solution thereof or alcoholic solution, hydroxypropyl methylcellulose and aqueous solution thereof or the starch slurry;

And lubricant;

Wherein, ulipristal acetate accounts for the 50-85% of premix material gross weight, and the particle diameter of the ulipristal acetate of 70-100% and disintegrating agent particle is less than or equal to 75 microns.

Excipient also comprises: sweeting agent, aromatic and coloring agent.

In filler preferred starch, lactose, microcrystalline Cellulose and the mannitol one or more.

The preferred low-substituted hydroxypropyl cellulose of disintegrating agent, carboxymethyl starch sodium and polyvinylpolypyrrolidone, wherein when disintegrating agent was polyvinylpolypyrrolidone, ulipristal acetate accounted for the 67-83% of premix material gross weight; When disintegrating agent was carboxymethyl starch sodium, ulipristal acetate accounted for the 50-55% of premix material gross weight.

The preparation method of pharmaceutical composition of the present invention:

1) micronized ulipristal acetate and particle diameter are pre-mixed (first disintegrating agent is sieved in case of necessity and remove large particle diameter adjuvant) less than 75 microns disintegrating agent, or common micronization after not micronized ulipristal acetate mixed with disintegrating agent, obtain the premix material of disintegrating agent and principal agent;

2) with 1) middle premix material and other excipient except binding agent and lubricant, utilize suitable mixing apparatus mix homogeneously;

3) add binding agent and carry out wet granulation, dry also with tabletting behind the suitable order number sieve net granulate, also can adopt one-step palletizing or dry granulation tabletting; Can not granulate, 2 yet) in add simultaneously place's binding agent, in this step, add mix lubricant and adopt direct powder compression after evenly.

When micronized ulipristal acetate particle and one or more particle diameters are pre-mixed less than 75 microns disintegrating agent, can select any hybrid mode, include but not limited to mix, ground and mixed, sieve and mix etc.; Can select any type of manual mixing, and the mixing of arbitrary preparation mixing apparatus, include but not limited to V-type blender, bicone blender, stir trough type mixing machine, taper vertical spin mixer etc.

In the time of will be without micronized ulipristal acetate and the common micronization of one or more disintegrating agents, any type of micronization technology be can select, ball milling, comminution by gas stream, supercritical fluid technology included but not limited to.

Beneficial effect of the present invention is:

1, the present invention adopts ulipristal acetate to remix behind the less disintegrating agent micronization of consumption or micronization, obtains the premix material of ulipristal acetate and disintegrating agent, has both solved the independent micronization existence of ulipristal acetate in the ulipristal acetate sheet

The principal agent loss amount is large, the problem of the difficult cleaning of equipment absorption, has prevented that again the micronization principal agent from assembling because particle diameter is too little, cause content inhomogeneous with the unsettled problem of stripping.

2, in the ulipristal acetate dispersible tablet of the present invention the particle diameter of the ulipristal acetate of 70-100% and disintegrating agent less than or equal to 75 microns, promoted that greatly raising and the stripping of ulipristal acetate dissolution are quick, wherein ulipristal acetate 5 minutes was basic all strippings in leachable 90%, 20 minute.

The specific embodiment

Embodiment 1

1) low-substituted hydroxypropyl cellulose is crossed 200 mesh sieves, and the particle of getting its fine powder and 70%-90% obtains the premix material of ulipristal acetate and low-substituted hydroxypropyl cellulose less than or equal to 50 microns ulipristal acetate manual mixing 10 minutes;

2) premix material again with lactose, microcrystalline Cellulose mix homogeneously in granulator;

3) add an amount of 5% hydroxypropyl methylcellulose granulation, 40 ℃ of dryings, granulate adds the magnesium stearate mix homogeneously, and tabletting makes 1000.

Check dispersing uniformity according to method under 2010 editions appendix IA of Chinese Pharmacopoeia item, the result meets the requirements.

Embodiment 2

1) particle of the 70%-90% ulipristal acetate less than or equal to 50 microns was mixed in granulator 5 minutes with polyvinylpolypyrrolidone Polyplasdone XL-10 (＜74 μ m), obtain the premix material of ulipristal acetate and polyvinylpolypyrrolidone;

2) again with mannitol and the microcrystalline Cellulose mix homogeneously of recipe quantity;

3) add the alcoholic solution granulation of an amount of 10% PVP K30,40-50 ℃ of drying, granulate adds the magnesium stearate mix homogeneously of recipe quantity, and tabletting makes 1000.

Check dispersing uniformity according to method under 2010 editions appendix IA of Chinese Pharmacopoeia item, the result meets the requirements.

Embodiment 3

1) at first the particle of 70%-90% is put less than or equal to 20 microns ulipristal acetate and the polyvinylpolypyrrolidone Kollidon Cl-M of recipe quantity (＜15 μ m account for more than 90%) and mixed 5 minutes in the granulator, obtain the premix material of ulipristal acetate and polyvinylpolypyrrolidone;

2) add recipe quantity lactose and microcrystalline Cellulose mixing 5 minutes in the premix material;

3) then add an amount of 5% hydroxypropyl methylcellulose aqueous solution granulation, 50-60 ℃ of drying behind the granulate, adds magnesium stearate and mixes, and tabletting makes 10000.

Check dispersing uniformity according to method under 2010 editions appendix IA of Chinese Pharmacopoeia item, the result meets the requirements.

Embodiment 4

1) will without comminution by gas stream behind the carboxymethyl starch sodium mix homogeneously of micronized ulipristal acetate and recipe quantity, obtain the particle of 70%-90% less than or equal to the ulipristal acetate of 75 microns (200 orders) and the premix material of carboxymethyl starch sodium;

2) in promoting the hopper mixer, mix all with lactose, microcrystalline Cellulose;

3) add magnesium stearate and Pulvis Talci again and mix, direct compression makes 1000.

Check dispersing uniformity according to method under 2010 editions appendix IA of Chinese Pharmacopoeia item, the result meets the requirements.

Embodiment 5

Ulipristal acetate 5g

Lactose starch premix material 89.0g

Carboxymethyl starch sodium 5.0g

Magnesium stearate 1.0g

1) cross-linking sodium carboxymethyl cellulose is crossed 200 mesh sieves, the particle of getting its fine powder and 70%-90% was less than or equal to 50 microns ulipristal acetate manual mixing 5 minutes, and cross twice mix homogeneously of 80 mesh sieves, obtain the premix material of ulipristal acetate and carboxymethyl starch sodium;

2) again with the lactose starch premix material mix homogeneously of recipe quantity after;

3) add the magnesium stearate mixing, tabletting makes 1000.

Check dispersing uniformity according to method under 2010 editions appendix IA of Chinese Pharmacopoeia item, the result meets the requirements.

Embodiment 6

Dissolution Rate Testing

Medicine: one group is the ulipristal acetate ordinary tablet (market is buied) of 30mg, and another group is the ulipristal acetate dispersible tablet according to example 2 disclosed 30mg of the present invention.

Assay method: get respectively each 6 of two groups of medicines, measure according to dissolution method (2010 editions two appendix X C of Chinese Pharmacopoeia first method), adopt the HCl of 0.1N to operate as dissolution medium in accordance with the law, respectively at 0,5,10,20,30,45,60min, sampling and measuring, get its meansigma methods, the result is as follows:

The ulipristal acetate sheet in time (minute) stripping (%)

Time (min)	0	5	10	20	30	45	60
								Ordinary tablet	0	71	83	89	91	93	93
Dispersible tablet	0	86	92	99	99	100	100

As can be seen from the above table, the dissolution rate of the ordinary tablet that ulipristal acetate dispersible tablet of the present invention is more commercially available is significantly accelerated, and got final product basic all strippings in 20 minutes, and ordinary tablet reaches platform in the time of 45 minutes, and only stripping 93%.

Claims (7)

1. ulipristal acetate dispersible tablet comprises:

The premix material of ulipristal acetate and disintegrating agent, ulipristal acetate content are 1-30% (w/w);

Filler: one or more in sucrose, dextrin, lactose, mannitol, sorbitol, microcrystalline Cellulose, starch, calcium sulfate, the calcium hydrogen phosphate, filler content are 10-90% (w/w);

Disintegrating agent: one or more in polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, microcrystalline Cellulose, starch and the derivant thereof;

Binding agent: one or both in polyvidone and aqueous solution thereof or alcoholic solution, hydroxypropyl methylcellulose and aqueous solution thereof or the starch slurry;

And lubricant;

Wherein, ulipristal acetate accounts for the 50-85% of premix material gross weight, and the particle diameter of the ulipristal acetate of 70-100% and disintegrating agent particle is less than or equal to 75 microns.

2. pharmaceutical composition according to claim 1, it is characterized by disintegrating agent is low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium and polyvinylpolypyrrolidone.

3. pharmaceutical composition according to claim 2, it is characterized by disintegrating agent is polyvinylpolypyrrolidone, ulipristal acetate accounts for the 67-83% of premix material gross weight.

4. pharmaceutical composition according to claim 2, it is characterized by disintegrating agent is carboxymethyl starch sodium, ulipristal acetate accounts for the 50-55% of premix material gross weight.

5. according to claim 3 or 4 described pharmaceutical compositions, it is characterized by filler and be in starch, lactose, microcrystalline Cellulose and the mannitol one or more.

6. the preparation method of the described pharmaceutical composition of claim 1-5 any one comprises the steps:

1) micronized ulipristal acetate and the particle diameter disintegrating agent less than 75 microns is pre-mixed, obtains the premix material of disintegrating agent and principal agent;

2) with 1) middle premix material and other excipient except binding agent and lubricant, utilize suitable mixing apparatus mix homogeneously;

3) add binding agent and carry out wet granulation, dry also with tabletting behind the suitable order number sieve net granulate; Or employing one-step palletizing or dry granulation tabletting; Or do not granulate, 2) in add simultaneously place's binding agent, in this step, add mix lubricant and adopt direct powder compression after evenly.

7. the preparation method of the described pharmaceutical composition of claim 1-5 any one comprises the steps:

1) not micronized ulipristal acetate is mixed rear common micronization with disintegrating agent, obtain the premix material of disintegrating agent and principal agent;

2) with 1) middle premix material and other excipient except binding agent and lubricant, utilize suitable mixing apparatus mix homogeneously;

3) add binding agent and carry out wet granulation, dry also with tabletting behind the suitable order number sieve net granulate; Or employing one-step palletizing or dry granulation tabletting; Or do not granulate, 2) in add simultaneously place's binding agent, in this step, add mix lubricant and adopt direct powder compression after evenly.